A study on antioxidant and hepatoprotective activity of hydroalcoholic extract of Hylocereus undatus fruits against acetaminophen and ethanol induced hepatotoxicity was conducted in experimental rats. Two doses 250mg/kg and 500mg/kg, p.o. of the extract were subjected for the evaluation of hepatoprotective potential against acetaminophen (2g/kg) and ethanol (2ml/100g) induced liver injury. Silymarin (25mg/kg) was used as a standard drug. The parameters like SGPT, SGOT, ALP, total bilirubin, direct bilirubin and endogenous enzymes were estimated to assess the liver functions. Both the lower (250mg/kg) and higher dose (500mg/kg) of Hylocereus undatus fruit extract showed dose dependent significant decrease in SGPT, SGOT, ALP, total bilirubin and direct bilirubin levels when compared with toxic control. Both the doses showed decrease in LPO and increase in GSH levels. The present study concluded that Hylocereus undatus fruit was found to be effective against hepatotoxicity induced by acetaminophen and ethanol. Further studies are needed to isolate and characterize the active principles and to find out the mechanism responsible for its hepatoprotective activity.